IL-7 and Lymphocyte Homeostasis: Life versus Death

描述（由申请人提供）：免疫系统的内稳态是通过促生和促死信号的平衡来维持的，细胞因子白介素-7 （IL-7）是限制种群规模的关键资源。细胞死亡是消除健康组织中异常细胞的必要过程。细胞的生长是通过调节细胞的生命周期和代谢来调节的。通过探索IL-7的这些生物活性，本研究拓展了对癌症起源的认识。这些研究的主要发现将发展成为一个创新的研究项目，旨在研究IL-7在淋巴瘤形成中的作用。待验证的假设是，IL-7通过抑制BCL-2家族的凋亡蛋白，同时通过磷酸酶Cdc25A调节细胞循环，并通过葡萄糖摄取维持代谢资源，从而促进生命。IL-7的缺失触发凋亡蛋白BAX，该蛋白被BCL-2抑制。研究表明，凋亡蛋白BIM可能是IL-7信号的靶点，并调节BAX和BCL-2的效应活性。这将通过检查淋巴细胞中BIM的活性来确定- IL-7如何调节BIM以及BIM如何与其他BCL-2家族成员相互作用。IL-7作为增殖因子的活性将通过检查磷酸酶Cdc25A的调节和功能来研究，Cdc25A是细胞周期的关键介质。为了确定Cdc25A的稳态潜能，将评估表达活性、稳定形式Cdc25A的细胞在IL-7缺乏环境中的生长情况。IL-7的存活和增殖活动可能与能量资源的维持有关。通过IL-7信号传导介导葡萄糖摄取的因素将在细胞凋亡被抑制或细胞分裂被诱导的细胞中进行研究。所提出的方法结合了小鼠实验的使用，建立了生理相关性，并使用细胞系进行功能分析，以检查IL-7对外周细胞稳态至关重要的活性的机制。预期结果将对细胞因子研究领域产生重大影响。

DESCRIPTION (provided by applicant): Homeostasis of the immune system is maintained through a balance of pro-life and pro-death signals, with availability of the cytokine, interleukin-7 (IL-7), a critical resource limiting population size. Cell death is a necessary process that eliminates abnormal cells in healthy tissue. Cell growth is mediated by regulation of the cell life cycle and metabolism. By exploring these biological activities of IL-7, this proposal expands the understanding of the origins of cancer. Key findings from the proposed studies will be developed into an innovative research program designed to study the role of IL-7 in lymphomagenesis. The hypothesis to be tested is that IL-7 promotes life by repressing apoptotic proteins of the BCL-2 family, while regulating cell cycling through the phosphatase, Cdc25A, and maintaining metabolic resources through glucose uptake. Loss of IL-7 triggers the apoptotic protein, BAX, which is inhibited by BCL-2. Studies suggest that the apoptotic protein, BIM, could be a target of IL-7 signaling and modulate the effector activities of BAX and BCL-2. This will be determined by examining the activity of BIM in lymphocytes - how IL-7 regulates BIM and how BIM interacts with other BCL-2 family members. The activity of IL-7 as a proliferative factor will be studied by examining the regulation and function of the phosphatase, Cdc25A, a key mediator of cell cycling. To establish the homeostatic potential of Cdc25A, cells expressing an active, stable form of Cdc25A will be evaluated for growth in an IL-7 deficient environment. The survival and proliferative activities of IL-7 may be supported by maintenance of energy resources. The factors mediating glucose uptake through IL-7 signaling will be examined in cells in which apoptosis has been inhibited or cell division induced. The approaches proposed combine the use of mouse experiments that establish physiological relevance with functional assays using cell lines to examine mechanisms underlying the activities of IL-7 essential for the homeostasis of peripheral cells. Expected findings will have significant impact in field of cytokine research.